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The Scientific Basis of Medicine
Published in John S. Axford, Chris A. O'Callaghan, Medicine for Finals and Beyond, 2023
Chris O'Callaghan, Rachel Allen
DNA strands consist of nucleotides joined by phosphodiester bonds linking the sugar of one nucleotide to the phosphate group of the next. DNA coils into a double helix of two antiparallel strands (Figure 2.1). Complementary base pairing of adenine with thymine and guanine with cytosine ensures the fidelity of DNA transcription and replication. When DNA is copied, each parental strand acts as a template for replication: incoming nucleotides form hydrogen bonds with an appropriate base on the template strand. Base mispairing, induced by damage or mutation, introduces structural alterations which can be detected and/or removed by DNA repair proteins.
Cellular and Immunobiology
Published in Karl H. Pang, Nadir I. Osman, James W.F. Catto, Christopher R. Chapple, Basic Urological Sciences, 2021
Masood Moghul, Sarah McClelland, Prabhakar Rajan
Each nucleotide base can only bond with one type of base (base pairing):G⇔CA⇔T/A⇔U in RNA
The Fight Against Cancer
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Before cell division can occur, DNA replication must take place so that the genetic material can be passed to the daughter cells. DNA unwinds ready for replication, then the two strands are ‘unzipped’ by the enzyme DNA helicase, which breaks the hydrogen bonds between bases. The exposed bases of each strand can now undergo complimentary base pairing with free nucleotides in the nucleus, which are assembled by another enzyme, called DNA polymerase. Finally, all the nucleotides are combined to form two new polynucleotides; each comprised of an original strand and a new strand. This is called semi-conservative replication.
Plant-Derived Natural Non-Nucleoside Analog Inhibitors (NNAIs) against RNA-Dependent RNA Polymerase Complex (nsp7/nsp8/nsp12) of SARS-CoV-2
Published in Journal of Dietary Supplements, 2023
Sreus A. G. Naidu, Ghulam Mustafa, Roger A. Clemens, A. Satyanarayan Naidu
In CoVs, RdRp catalyzes the synthesis of the RNA genome using the (+)RNA strand as a template to produce a complementary (−)RNA strand starting from 3′-poly-A tail (19). There are two plausible molecular mechanisms to initiate the genomic RNA synthesis by RdRp: i) the primer-independent (de novo) synthesizes the genomic RNA by forming a phosphodiester bond with 3′-hydroxyl group linked to 5′-phosphate group of the adjacent nucleotide (49); and ii) the primer-dependent synthesis generates a new RNA complementary to the template with base pairing under the guidance of either an oligonucleotide or a protein primer (50). Furthermore, four cellular ribonucleotide triphosphates (rNTPs), ATP, GTP, CTP, and UTP provide the template substrates, which are recognized by RdRp. Divalent metal ions magnesium (Mg2+) and manganese (Mn2+) act as essential cofactors in the polymerization reaction and coordinate the catalytic aspartates to promote reactivity with rNTPs (51).
Discovery of RNA-targeted small molecules through the merging of experimental and computational technologies
Published in Expert Opinion on Drug Discovery, 2023
RNA-observed NMR techniques provide a wealth of information regarding how a ligand interacts with its target RNA, and such information is extremely helpful for understanding the mechanism of recognition and rational design. The most straightforward method is chemical shift mapping with 1H NMR spectroscopy using the imino proton region, in which the perturbations in the solvent exchangeable H1 of guanosines and H3 of uridines can be monitored upon gradual addition of the ligand (Figure 4(e)) [148]. The H1 and H3 imino protons serve as hydrogen donors in base pairing interactions and are, thus, perturbed when a small molecule interacts with the RNA. Because of the distinct chemical shift ranges and minimal spectroscopic overlap, perturbations in these imino protons can be monitored in a simple 1D manner. One disadvantage of imino 1H NMR spectroscopy is that, because the unstructured imino protons cannot be observed, it cannot detect perturbations when they occur at the loops and bulges on the RNA. To monitor more changes in the RNA brought about by small-molecule binding, it is advisable to pair imino-based NMR characterizations with 2D 1H-1H total correlated spectroscopy (TOCSY, otherwise known as Homonuclear Hartmann-Hahn or HOHAHA). This method measures the H5–H6 cross-peak of pyrimidines (Figure 4(e)), and since the H5 and H6 protons are non-solvent exchangeable and carbon-bound, TOCSY can robustly monitor perturbations even those of pyrimidines in unstructured loops and bulges.
Microsatellite instability and oncological outcomes in Thai patients with endometrial cancer
Published in Journal of Obstetrics and Gynaecology, 2022
Thiti Atjimakul, Panote Wattanapaisal, Supaporn Suwiwat, Worrawit Wanichsuwan, Jitti Hanprasertpong
Endometrial cancer (EC) was included as a common gynaecological cancer in the Global Cancer Statistics report in 2020; over 417,367 new cases were reported in 2020 (Sung et al. 2021). The National Cancer Institute of Thailand has also reported EC as the third most common gynaecological cancer in the Thai female population, with three per 100,000 cases per year (Virani et al. 2017). Most ECs occur sporadically, with only 3–5% being related to germline mutation (Thibodeau et al. 1993; Herman et al. 1998; Boland et al. 2008). Genetic alterations in EC are frequently associated with the loss of mismatch repair (MMR) system. The latter involves a repetitive DNA sequence-repair mechanism that maintains genomic integrity by correcting base substitutions and minor insertion–deletion mismatches generated due to base-pairing errors by DNA polymerase during replication. Mutations in MMR genes, such as mutL homolog 1 (MLH1); mutS homologs 6 (MSH6), 2 (MSH2) and 3 (MSH3); and PMS1 homolog 2 (PMS2), assemble as microsatellite sequences throughout the genome, a phenomenon realised as microsatellite instability (MSI) (Lower et al. 2018).